title: The endophenotype and the phenotype: temporal discrimination and adult-onset dystonia.
abstract: The pathogenesis and the genetic basis of adult-onset primary torsion dystonia remain poorly understood. Because of markedly reduced penetrance in this disorder, a number of endophenotypes have been proposed; many of these may be epiphenomena secondary to disease manifestation. Mediational endophenotypes represent gene expression; the study of trait (endophenotypic) rather than state (phenotypic) characteristics avoids the misattribution of secondary adaptive cerebral changes to pathogenesis. We argue that abnormal temporal discrimination is a mediational endophenotype; its use facilitates examination of the effects of age, gender, and environment on disease penetrance in adult-onset dystonia. Using abnormal temporal discrimination in unaffected first-degree relatives as a marker for gene mutation carriage may inform exome sequencing techniques in families with few affected individuals. We further hypothesize that abnormal temporal discrimination reflects dysfunction in an evolutionarily conserved subcortical-basal ganglia circuit for the detection of salient novel environmental change. The mechanisms of dysfunction in this pathway should be a focus for future research in the pathogenesis of adult-onset primary torsion dystonia.
authors.affiliation: Department of Neurology, St. Vincent's University Hospital, Dublin, Ireland; University College Dublin, Dublin, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Hutchinson
authors.forename: Okka
authors.initials: O
authors.lastname: Kimmich
authors.forename: Anna
authors.initials: A
authors.lastname: Molloy
authors.forename: Robert
authors.initials: R
authors.lastname: Whelan
authors.forename: Fiona
authors.initials: F
authors.lastname: Molloy
authors.forename: Tim
authors.initials: T
authors.lastname: Lynch
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Healy
authors.forename: Cathal
authors.initials: C
authors.lastname: Walsh
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Edwards
authors.forename: Laurie
authors.initials: L
authors.lastname: Ozelius
authors.forename: Richard B
authors.initials: RB
authors.lastname: Reilly
authors.forename: Seán
authors.initials: S
authors.lastname: O'Riordan
mesh_terms: D000328:Adult; D004192:Discrimination, Psychological; D004421:Dystonia / Q000175:diagnosis / Q000503:physiopathology / Q000523:psychology; D006801:Humans; D010641:Phenotype
keywords: focal dystonia; mediational endophenotype; phenotype; putamen; temporal discrimination